Treatment of patients with chronic hepatitis C with recombinant interferon alfa (rIFN-α) can cause a decrease of serum transaminases and hepatitis C virus (HCV) RNA. Recent trials evaluating combination therapy of IFN-α and ribavirin suggested a potential synergistic effect. From serial measurements of serum HCV RNA concentrations following treatment-induced perturbation of the balance between virus production and clearance, we compared the antiviral efficacy of both IFN-α alone and IFN-α in combination with ribavirin. Chronically HCV-infected patients were treated with either 3 × 3 MU or 3 × 6 MU rIFN-α per week or 3 × 6 MU rIFN-α plus 14 mg/kg of body weight ribavirin per day. The time-dependent HCV RNA concentrations during antiviral treatment were analyzed by iterative least-squares regression. After initiation of antiviral therapy, HCV RNA declined exponentially below the detection limit of the reverse-transcription polymerase chain reaction assay (1,000 HCV RNA molecules per milliliter) in 10 of 26 (39%), 10 of 19 (53%), and 10 of 18 patients (56%) treated with 3 × 3 MU, 3 × 6 MU rIFN-α without and with ribavirin, respectively. Viral clearance from serum was faster in patients treated with 3 × 6 MU rIFN-α (t1/2 = 0.23 ± 0.15) compared with patients treated with 3 × 3 MU rIFN-α per week (0.67 ± 0.36 days) (P < .004). However, half-lives of viral clearance were similar in patients treated with rIFN-α or rIFN-α plus ribavirin. For virus release from infected hepatocytes, absence and presence of ribavirin yielded half-lives of t1/2= 2.54 ± 2.10 and t1/2 = 1.99 ± 1.70, respectively, indicating that ribavirin does not significantly inhibit HCV production. In conclusion, the data of the present study indicate that higher rIFN-α doses accelerate viral clearance from serum. Ribavirin (14 mg/kg/d), however, lacks synergistic antiviral effects in the treatment of chronic hepatitis C with 3 × 6 MU rIFN-α per week.